The ECDC point of view on the requests from the European Commission

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1 The ECDC point of view on the requests from the European Commission Anna-Pelagia Magiorakos, MD, FIDSA, Senior Expert AMR and HAI for ARHAI Disease Programme European Centre for Disease Prevention and Control EMA, London, United Kingdom, 28 February, 2014

2 Source: Center for Global Development The Race Against Drug Resistance Boucher et al. Clin Infect Dis Jan 1;48(1):1-12 A Global concern of antimicrobial resistance *Emergence and spread of new mechanisms of resistance * Antimicrobial misuse Drug regulation Human and animal antimicrobial misuse * No new antimicrobials in the development pipeline * Cycle: antimicrobial use resistance antimicrobial use

3 The ecological phenomenon of resistance Resistance in commensal and pathogenic organisms reservoirs for resistant genes Dissemination of resistant bacteria and mobile genetic elements Koike et al. Monitoring and Source tracking of Tetracycline Resistance Genes in Lagoons and Groundwater Adjacent to Swine Production Facilities. Horizontal transfer of mobile genetic elements to pathogenic bacteria in the animal and human gut Adapted from: Witte W. Int J Antimicrob Agents; 2000;14(4):321-5 Koike et al. Applied and Environmental Microbiology, 73 (15): (2007).

4 Burden and outcomes of infections with multidrug-resistant (MDR) bacteria in the EU, Iceland and Norway Human burden Infections (6 most frequent MDR bacteria, 4 main types of infection) approx. 400,000 / year Attributable deaths approx. 25,000 / year Extra hospital days approx. 2.5 million / year Economic burden Extra in-hospital costs Productivity losses approx. 900 million / year approx. 600 million / year Limitation: these are underestimates. Source: ECDC, In:

5 Carbapenemases: main types of enzymes Acronym Name or type First isolated KPC Klebsiella pneumoniae carbapenemase 1996 VIM Verona integron-encoded metallo-beta-lactamase 1997 OXA-48 OXA-type carbapenemase 2001 NDM-1 New Delhi metallo-beta-lactamase 2008 ECDC/EMEA. Boucher et al. Clin Infect Dis Jan 1;48(1):1-12

6 Bacterium MDR XDR PDR Staphylococcus aureus The isolate is non-susceptible to at least 1 agent in 3 antimicrobial categories listed in Table 1a * The isolate is non-susceptible to at least 1 agent in all but 2 or fewer antimicrobial categories in Table 1a. Non-susceptibility to all agents in all antimicrobial categories for each bacterium in Tables 1a-1e Enterococcus spp. The isolate is non-susceptible to at least 1 agent in 3 antimicrobial categories listed in Table 1b The isolate is non-susceptible to at least 1 agent in all but 2 or fewer antimicrobial categories in Table 1b. Enterobacteriaceae Pseudomonas aeruginosa Acinetobacter spp. The isolate is non-susceptible to at least 1 agent in 3 antimicrobial categories listed in Table 1c The isolate is non-susceptible to at least 1 agent in 3 antimicrobial categories listed in Table 1d The isolate is non-susceptible to at least 1 agent in 3 antimicrobial categories listed in Table 1e The isolate is non-susceptible to at least 1 agent in all but 2 or fewer antimicrobial categories in Table 1c. The isolate is non-susceptible to at least 1 agent in all but 2 or fewer antimicrobial categories in Table 1d. The isolate is non-susceptible to at least 1 agent in all but 2 or fewer antimicrobial categories in Table 1e. Magiorakos et al. CMI, 2011.

7 Inappropriate, delayed or inadequate therapy Adapted from: Kollef et al.1999 Adapted from: Micek et al.2011 Kumar et al. Chest Kollef et al. Chest Micek et al. J Hosp Med. 2011

8 Critically important antimicrobials for human medicine 1) Antimicrobial agent is used as sole therapy or one of few alternatives to treat serious human disease. 2) Antimicrobial agent is used to treat diseases caused by either: (1) organisms that may be transmitted via non-human sources or (2) diseases causes by organisms that may acquire resistance genes from non-human sources. Serious disease: one that if left untreated are likely to result in irreversible morbidity or mortality Evidence for link of transmission is highest for Enterococcus, E. coli, S. aureus, Salmonella spp., Campylobacter spp. (and environmental sources) Organisms that cause disease need not be resistant at present; however, the potential for transmission shows the path for acquisition now or in the future" Critically Important antimicrobials for human medicine. WHO. 3 rd revision. 2011

9 Critically important antimicrobials for human medicine Prioritizing strategies to preserve their effectiveness in human medicine. Ensuring that critically important antimicrobials are included in antimicrobial susceptibility monitoring programmes. Refining and prioritizing risk profile and hazard analysis activities for interventions by species or by region. Developing risk management options such as restricted use, labelling, limiting or prohibiting extra-label use, and making antimicrobial agents available by prescription only. For the development of prudent use and treatment guidelines in humans and animals. To direct special research projects to address prevalence data gaps on existing or potential future CIAs. Critically Important antimicrobials for human medicine. WHO. 3 rd revision. 2011

10 Escherichia coli: percentage of invasive isolates resistant to third-generation cephalosporins; EU/EEA, Source: EARS-Net, 2013 The symbols and indicate a significant increasing or decreasing trend for the period , respectively. These trends were calculated on laboratories that consistently reported during

11 Paolo (Italy)

12 Resistant to gentamicin, cipro, 3 rd gen ceph Pre-travel colonisation 7.8%, post- travel 49% E. coli: percentage of invasive isolates resistant to fluoroquinolones EU/EEA, 2012 Kennedy K, Collignon P. Eur J Clin Microbiol Inf Dis, 2010 Chong Y et al. PLoS ONE, 2014

13 EU/EEA mean resistance percentage 2012 (population-weighted*) 6.2% Carbapenems Carbapenems < 0.1% K. pneumoniae Aminoglycosides 22.2 % E. coli Aminoglycosides 10.3 % Third-gen cephalosporins 25.7 % Fluoroquinolones 25.3 % Third-gen cephalosporins 11.8 % Fluoroquinolones 22.3 % Combined resistance (3GC+FQ+AG) 18.5% Combined resistance (3GC+FQ+AG) 4.4% *) Population-based weights applied to each national estimate before calculating arithmetic mean for EU/EEA

14 Carbapenem consumption* (for the large majority in hospitals); EU/EEA, *in Defined Daily Doses per 1000 inhabitants and per day 2010 Source: ESAC-Net, 2012 The symbols and indicate a significant increase or decrease between 2007 and 2010, respectively. These trends are indicated only for countries that reported relevant data for both 2007 and 2010.

15 Klebsiella pneumoniae: percentage of invasive isolates resistant to carbapenems; EU/EEA, Source: EARS-Net, 2013 The symbols and indicate a significant increasing or decreasing trend for the period , respectively. These trends were calculated on laboratories that consistently reported during

16 Mohammed (United Kingdom)

17 Country self-assessment of stages for spread of carbapenemase-producing Enterobacteriaceae (all isolates), 2010 and 2013 Flickr-mardrom1 Source: Grundmann et al. Eurosurveill 2010, and The symbols and indicate a positive or negative change in stage between 2010 and EuSCAPE project, Glasner et al., Eurosurveill This change could only be indicated for countries that reported for both years.

18 Boo TW et al. Eurosurveillance, 2013; Mahableshwar A. AAC Capone et al. CMI, 2013

19 Identification In Proteus Mirabilis of a Salmonella Genomic Island Containing the blandm-1 Carbapenemase Gene Together with the ESBL-encoding Gene blaveb-6 L. Dortet, L. Poirel, P. Nordmann; Hosp. de Bicetre, Le Kremlin Bicetre, FRANCE. Scientific Opinion on carbapenem resistance in food animal ecosystems. EFSA Panel on Biological Hazards on Biological Hazards (BIOHAZ). EFSA Journal 2013;11(12):3501 Woodford et al JAC, 2014 Dortet et al. ICAAC Abstracts, 2013

20 Perspectives Need for well-performed studies documenting transmission Need for good surveillance of AMR in animals Control options for misuse in animal husbandry "When a new class of drug comes on the market, it should be considered critically important unless strong evidence suggests otherwise "Existing drugs e.g. carbapenems, linezolid, and daptomycin, not currently used in food production, should not be used in the future in animals, plants, or in aquaculture. Critically Important antimicrobials for human medicine. WHO. 3 rd revision. 2011

21 Key points in creating a response to Question 2 1. Modified terminology: "limited therapy for" necessary for 1. Broaden clinical indications in which antibiotics are used 2. Need for antibiotics in humans needs to be highlighted 3. Ensure that evidence-based data included for transmission 4. Highlight changes in epidemiology/new resistance mechanisms can be found in zoonotic bacteria (e.g. NDM in Salmonella spp.) 5. Need for good surveillance data for AMR in animals 6. Need for a gap analysis of alternatives before suggesting new antimicrobials 8. When a new class of drug comes on the market, it should be considered critically important unless strong evidence suggests otherwise Critically Important antimicrobials for human medicine. WHO. 3 rd revision. 2011

22 Acknowledgments ECDC Antimicrobial Resistance and Healthcare-Associated Infections (ARHAI) Disease Programme: Dominique Monnet Carl Suetens Klaus Weist Liselotte Diaz Högberg Barbara Albiger Marc Struelens Ole Heuer Diamantis Plachouras Pete Kinross Pierluigi Lopalco

23 Thank you